This invention relates to a novel N-acetyl substituted aryl analog of an N-substituted benzamide, its acid addition salts, the use thereof as direct chemotherapeutic agents or as sensitizers for radiation and/or other chemotherapeutic agents in methods of inhibiting or killing tumor and cancer cells in human patients or other warm-blooded animals, and also the use thereof as anti-inflammatory agents in methods of treating inflammatory disorders in human patients or other warm-blooded animals.
The invention described in the aforementioned application Ser. No. 08/807,497 ("the '497 application") , in a first aspect, broadly contemplates the provision of a method of inhibiting or killing tumor or cancer cells in a human patient, consisting essentially of treating the patient with a composition selected from the group consisting of aryl N-substituted carboxamides having one or more aryl halo or one or more aromatic nitrogens, acid addition salts of these carboxamides, and mixtures thereof. In this method, the defined carboxamides act directly as chemotherapeutic agents, not merely as sensitizers for radiation and other chemotherapeutic agents. The term "consisting essentially," as used in the definition of the above-described method, excludes the use or presence of radiation or chemotherapeutic agents (other than the stated carboxamides and/or acid addition salts thereof) in the practice of the method.
The invention of the '497 application in a second aspect contemplates the provision of a method of inhibiting or killing tumor or cancer cells in a human patient, consisting essentially of treating the patient with radiation or a chemotherapeutic agent together with a composition selected from the group consisting of N-substituted nicotinamides, N-(2-diethylamino-ethyl)-4-amino-3-chlorobenzamide (hereinafter sometimes referred to as 3-chloroprocainamide or 3-CPA), their acid addition salts, and mixtures thereof, in an amount effective to enhance the cytotoxicity of the radiation or chemotherapeutic agent employed. The selected composition, in the latter method, acts as a sensitizer for the radiation or chemotherapeutic agent. The compositions used as such sensitizers are within the broadly defined class of aryl N-substituted carboxamides having one or more aryl halo or one or more aromatic nitrogens.
In further important specific aspects, the invention of the '497 application contemplates the provision of certain novel compositions within the last-mentioned class and suitable for use in the practice of one or more of the above-stated methods; and the use of such compositions in the same methods. These compositions include the compound N-(2-diethylamino-ethyl) nicotinamide (which is an N-substituted nicotinamide, hereinafter sometimes referred to as N-NAM), its acid addition salts, acid addition salts of N-(2-diethylamino-ethyl)-4-amino-3-chlorobenzamide (i.e., 3-chloroprocainamide, mentioned above), and mixtures thereof. Preferred acid addition salts are the hydrochlorides, viz., N-(2-diethylaminoethyl) nicotinamide HCl and 3-chloroprocainamide HCl.
Stated broadly, the invention of the '497 application in significant aspects is based on the identification of chemical features that impart properties of radio- and chemosensitization to some members of the group of agents discussed in the above-cited prior art, and embraces the discovery that agents having such properties include a new class of drugs called the N-substituted nicotinamides (e.g. N-NAM).
The invention described in the aforementioned application Ser. No. 08/807,071 ("the '071 application"), in one broad sense, embraces the discovery that at least some benzamides and nicotinamides can selectively induce apoptosis without having any significant effects on necrosis, 1997), and that benzamides and nicotinamides (i.e., other than benzamides with N-pyridinyl substitutions) are useful as anti-inflammatory drugs.
By way of partial explanation of the latter discovery, it may be noted that apoptosis is a normal physiological mechanism contributing to the inflammatory development of several disorders including but not limited to cancer, HIV/AIDS, psoriasis, Alzheimer's disease, Hodgkin's disease, Huntington's chorea, ischemic injury, and many other autoimmune and neurodegenerative diseases (Thompson, Science 267: 1456-1462, 1995); hence, the ability of at least some benzamides and nicotinamides to selectively induce apoptosis without having significant effect on necrosis suggests that the benzamides and nicotinamides may be useful as antiinflammatory drugs.
Also pertinent to an understanding of the foregoing may be the discussions of the molecular biology of inflammation and apoptosis presented in Science 274: 782-789 (Nov. 1, 1996), which set forth that the transcription factor known as nuclear factor kappa B (NF-.kappa.B) both inhibits the primary pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-.alpha.), and induces apoptotic killing of cells important to the development of new cancer chemotherapeutic strategies. As the benzamides and nicotinamides, particularly the N-substituted analogs, selectively induce apoptosis, then NF-.kappa.B inhibition being a known regulator of apoptosis may also inhibit the inflammatory response by likewise inhibiting TNF-.alpha. production in inflammatory target cells.
More particularly, the invention of the '071 application embraces the discovery that this is the case, i.e., that both the induction of apoptosis and the inhibition of TNF-.alpha. are mediated by the benzamides and nicotinamides giving this class of compounds both anti-cancer and anti-inflammatory properties.
The practice of the invention of the '071 application entails the use of administering to a human or other warm blooded animal: (i) that suffers from an inflammatory disorder such as but not limited to systemic lupus erythromatosis, rheumatoid arthritis, asthma, sepsis, ulcerative colitis, HIV/AIDS, psoriasis, Alzheimer's disease, Hodgkin's disease, Huntington's chorea, ischemic injury, (ii) by an appropriate route such as orally, intravenously, intramuscularly or subcutaneously, (iii) an amount of a benzamide or nicotinamide analog (other than benzamides with N-pyridinyl substitutions) either in a single or repeated dose schedule satisfactory to inhibit TNF-.alpha. production in vivo, (iv) that would inhibit the inflammatory response, and (v) that in turn would provide preventive or therapeutic value in controlling health disorders. In another aspect, the invention of the '071 application embraces the discovery that the composition of all benzamide and nicotinamide analogs, other than benzamides that have N-pyridinyl substitutions, are useful in preventing TNF-.alpha. production and thus they induce an anti-inflammatory response and have potential preventive or therapeutic value in the clinic. Furthermore, the invention of the '071 application embraces the discovery that benzamides in general and specifically the N-substituted benzamides, other than the pyridinyl-N-substituted benzamides, possess the potent anti-inflammatory properties of inhibiting the production of TNF-.alpha. and inducing apoptosis.
Thus, in one sense, the invention of the '071 application contemplates the provision of a method of treating inflammatory disorders comprising administering, to a human or other animal suffering from an inflammatory disorder, an amount of a composition selected from the group consisting of benzamide and nicotinamide analogs and mixtures thereof, other than benzamides with N-pyridinyl substitutions, such amount being effective to inhibit TNF-.alpha. production, thereby to inhibit an inflammatory response in the treated human or other animal.
Also in accordance with the invention of the '071 application, in certain advantageous embodiments thereof, the composition comprises, in combination, at least one compound selected from the group consisting of N-substituted benzamides and nicotinamides, other than benzamides with N-pyridinyl substitutions, that can inhibit TNF-.alpha. production in the presence of or as a consequence of pro-apoptotic stimuli and at least one compound selected from the group consisting of benzamide and nicotinamide analogs that can inhibit TNF-.alpha. in the absence of pro-apoptotic stimuli.
Additionally, the invention of the '071 application contemplates the provision of an anti-inflammatory agent comprising, in combination, at least one compound selected from the group consisting of N-substituted benzamides and nicotinamides, other than benzamides with N-pyridinyl substitutions, that can inhibit TNF-U production in the presence of or as a consequence of pro-apoptotic stimuli and at least one compound selected from the group consisting of benzamide and nicotinamide analogs that can inhibit TNF-.alpha. in the absence of pro-apoptotic stimuli.
Specifically, as stated in the '071 application, it is found that those N-substituted benzamides and N-substituted nicotinamides that exhibit the property of radiosensitization (e.g., metoclopramide, 3-chloroprocainamide, and 2-methoxy-N- (2-diethyl-aminoethyl) nicotinamide) can inhibit TNF-.alpha. production in the presence of or as a consequence of pro-apoptotic stimuli, while benzamides and nicotinamides other than the N-substituted analogs that exhibit the radiosensitizing property can inhibit TNF-.alpha. in the absence of pro-apoptotic stimuli.